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MOLECULAR MECHANISM OF TRANSFORMING GROWTH FACTOR-β
SIGNALING IN SKIN WOUND HEALING
by
Arum Han
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(GENETIC, MOLECULAR AND CELLULAR BIOLOGY)
December 2011
Copyright 2011 Arum Han

TGF-beta is a secreted cytokine, which plays an important role in cell development, differentiation, and homeostasis in both physiologic and pathologic conditions, such as tumorigenesis, abnormal wound healing and skin cancer. TGF-beta transmit signal from the extracellular environment to intracellular signaling networks via its cell surface receptor complex, the TGF-beta type II/ I receptor (TbetaRII/TbetaRI) heterodimer. TGF-beta ligand binds to TbetaRII, which in turn recruits and activates TbetaRI, resulting in activation of downstream signaling complex, receptor Smads (R-Smads) and common Smad4. TGF-beta stimulation is also known to activate R-Smad-independent signaling pathways, such as the extracellular signal-regulated kinase (ERK1/2) pathway. However, two long-standing questions remained: 1) why TGF-beta activates ERK depends on the cell context and 2) whether or not TbetaRII is able to mediate the TGF-beta signaling without the participation of TbetaRI. In the chapter two, it is shown that TGF-beta activates ERK in human dermal fibroblasts (DFs) and inhibits ERK in human keratinocytes (HKs). While the TbetaRI expression remains similar in both cell types, the expression level of TbetaRII in DFs is more than seven fold higher than that in HKs. Down-regulation of TbetaRII in DFs blocked TGF-beta-stimulated ERK activation. In contrast, up-regulation of TbetaRII in HKs to the similar level in DFs resulted in activation of ERK rather than inhibition by TGF-beta. Most intriguingly, the TbetaRII-mediated TGF-beta-stimulated ERK activation or inactivation in these cells did not require any participation of TbetaRI. Thus, this study illustrates that the vii expression levels of TbetaRII determine how TGF-beta regulates ERK in various cell types and provides direct evidence for the TbetaRI-independent signaling by TbetaRII. ❧ In wound healing, TGF-beta controls cell proliferation and migration. In the chapter three, the mechanism of TGF-beta's anti-motility was revealed. Anti-migration is one of the primary effects of TGF-beta on non-transformed cell types. We previously reported that TGF-beta3 inhibits PDGF-BB-induced dermal cell migration during wound healing. However, it was not clear what the underlying mechanism was. In this study, it is shown that TGF-beta3 activates PKA pathway through R-Smads/Smad4 complex. Activation of PKA led to over-expression and phosphorylation of paxillin, a focal adhesion molecule. As a result, polarization by PDGF-bb was disrupted and migration rate was decreased. This study elucidates the new mechanism of TGF-beta3 for inhibition of cell migration.

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MOLECULAR MECHANISM OF TRANSFORMING GROWTH FACTOR-β
SIGNALING IN SKIN WOUND HEALING
by
Arum Han
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(GENETIC, MOLECULAR AND CELLULAR BIOLOGY)
December 2011
Copyright 2011 Arum Han